Physico-chemical parameters that govern nanoparticles fate also dictate rules for their molecular evolution.

Nanoparticles are efficient to safely deliver therapeutic and imaging contrast agents to tumors for cancer diagnostic and therapy, if they can escape the reticuloendothelial system (RES) and accumulate in tumors either passively due to the enhanced permeability and retention (EPR) effect or actively via a specific ligand. The main hallmark of nanoparticles is their large surface areas, which, depending of their chemical compositions, surface coatings, electric charges, sizes and shapes, will generate complex, extremely dynamic and continuous interactions and exchanges between the nanoparticles and the different molecules present in the blood. Special attention will be paid to explain how the nanoparticles were improved step by step in order to adapt our increasing knowledge on their biophysics. In particular, we will discuss the influence of PEGylation, the difficulties to generate actively targeted particles and finally the actual trends in the manufacturing of "third-generation" smart particles.